Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions inducing differentiation of immature cells under development processes toward mature cells having specific functions, enhancement of cell proliferation and life support action. It has been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. (Sho)61-22047/1986 and (Sho)61-76440/1986, and the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p.2182. “Retinoids” is a general term for retinoic acid and the aforementioned compounds having retinoic acid-like biological activities.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cellular nucleus, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p.889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities (Petkovich, M., et al., Nature, 330, pp.444-450, 1987). It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities, for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]-benzoic acid: Am80, also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys. Res. Commun., 166, pp.1300-1307, 1990).
Clinically, these compounds were found to be useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia and certain types of cancer. However, due to the variety of biological activities of these retinoids, they are not fully satisfactory medicaments from a viewpoint of side effects. Therefore, it has been desired to create retinoids having characteristic activities and molecules controlling their activities.
As agents for controlling the activities of retinoids, benzodiazepine derivatives such as 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e](1,4]diazepin-11-yl]benzoic acid and 4-[1,3-dihydro-7,8-(2,5-dimethyl-2,5-hexano)-2-oxo-2H-1,4-benzodiazepin-5-yl] benzoic acid are known (PCT/JP96/2709, International Publication, WO97/11061). Furthermore, diphenylamine type compounds useful as agents for controlling the activities of retinoids are described on International Publication WO98/45242. Although these compounds, per se, have no retinoid action or their retinoid actions are feeble, they have remarkable enhancing actions on retinoids such as retinoic acid. Therefore, they have been suggested to be useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia, and certain types of cancer.
As for expression of physiological activities of retinoic acid, existence of retinoid X receptor (RXR, of which ligand is 9-cis-retinoic acid) has been verified. It has been revealed that the retinoid X receptor forms a dimer with the retinoic acid receptor (RAR) to induce or suppress gene transcriptions, thereby controls the expression of the physiological activities of retinoic acid (Mangelsdorf, D. J. et al., Nature, 345, pp.224-229). It has also been revealed that the retinoid X receptor (RXR) binds to the intranuclear receptor of active vitamin D3, PPAR whose involvement in lipid metabolism is suggested, and other receptors as well as to the retinoic acid receptor (RAR), thereby controls expression of actions of physiologically active substances binding to these receptors, for example, vitamin D3, thyroxine and the like (Mangelsdorf, D. J. et al., The Retinoids, 2nd Ed., Raven Press, pp.319-350, 1994).
As agents for controlling retinoid actions, compounds are also known to exist which have antagonistic action against retinoids and attenuate typical actions of the above retinoids (Eyrolles, L., et al., Journal of Medicinal Chemistry, 37(10), pp.1508-1517, 1994). The above publication discloses that some compounds such as 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[e]naphtho[2,3-b][1,4]-diazepin-13-yl)benzoic acid act as retinoid antagonists. Moreover, certain compounds including 4-(13H-10,11,12,13-tetrahydro-10,10,13,13,15-pentamethylnaphtho[2,3-b]1-[1,2-e][1,4]diazepin-7-yl)benzoic acid have been found as retinoid antagonists by the inventors of the present invention (specification of Japanese Patent Application No. (Hei)7-255912/1995).